The present invention relates to indole derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The active compounds of the present invention are useful in treating migraine and other disorders.
U.S. Pat. Nos. 4,839,377 and 4,855,314 and European Patent Application Publication Number 313397 refer to 5-substituted 3-aminoalkyl indoles. The compounds are said to be useful for the treatment of migraine.
British Patent Application 040279 refers to 3-aminoalkyl-1H-indole-5-thioamides and carboxamides. The compounds are said to be useful in treating hypertension, Raymond""s disease and migraine.
European Patent Application Publication Number 303506 refers to 3-poly:hydro-pyridyl-5-substituted-1H-indoles. The compounds are said to have 5-HT1 receptor agonist and vasoconstrictor activity and to be useful in treating migraine.
European Patent Application Publication Number 354777 refers to N-piperidinyl:indoyl:ethyl-alkane sulfonamide derivatives. The compounds are said to have 5-HT1 receptor agonist and vasoconstrictor activity and to be useful in treating cephalic pain.
European Patent Applications Publication Numbers 438230, 494774, and 49752 refers to indole-substituted five-membered heteroaromatic compounds. The compounds are said to have 5-HT1-like receptor agonist activity and to be useful in the treatment of migraine and other disorders for which a selective agonist of these receptors is indicated.
International Patent Application PCT/GB91/00908 and European Patent Application No. 313397A refers to 5-heterocyclic indole derivatives. The compounds are said to exhibit properties useful in the treatment and prophylaxis of migraine, cluster headache, and headache associated with vascular disorders. These compounds are also said to the xe2x80x9c5-HT1-likexe2x80x9d receptor agonism.
The present invention relates to compounds of the formula 
where W is 
n is 0, 1, or 2; m is 0, 1, 2, or 3; Y and G are each independently oxygen or sulfur; Z is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NH, or xe2x80x94CH2; R1 is hydrogen, C1 to C8 alkyl, substituted C1 to C8 alkyl substituted with one hydroxy, C3 to C8 alkenyl, C3 to C8 alkynyl, aryl, C1 to C3 alkylaryl, C1 to C3 alkyheteroaryl, or xe2x80x94Qxe2x80x94R4; R2 and R3 are each independently hydrogen, C1 to C8 alkyl, aryl, C1 to C3 alkylaryl, or C1 to C3 alkyheteroaryl; R4 is cyano, trifluoromethyl, xe2x80x94COR9, xe2x80x94CO2R9, xe2x80x94CONR9R10, xe2x80x94OR9, xe2x80x94SO2NR8R10, or xe2x80x94S(O)4R9; R9 and R10 are each independently hydrogen, C1 to C8 alkyl, C1 to C3 alkylaryl, aryl, or R9 and R10 may together be taken to form three-to seven-membered alkyl ring or a three- to seven-membered heteroalkyl ring having 1 heteroatom of O; R11 is hydrogen, xe2x80x94OR12, or xe2x80x94NHCOR12; R12 is hydrogen, C1 to C8 alkyl, aryl, or C1 to C3 alkyl-aryl; q is 0, 1, or 2; Q is C1 to C3 alkyl; a first chiral carbon is designated by an asterisk; a second chiral carbon is designated by #; and the above aryl groups and the aryl moieties of the above alkyl-aryl groups are independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C1 to C4 alkyl, halogen (e.g., fluorine, chlorine bromine or iodine), hydroxy, cyano, carboxamido, nitro, and C1 to C4 alkyoxy, and the pharmaceutically acceptable salts thereof. These compounds are useful in treating migraine and other disorders.
The compounds of the invention include all optical isomers of formula I (e.g., R and S sterogenicity at any chiral site) and their racemic, diastereomeric, or epimeric mixtures. The epimers with the S absolute configuration at the chiral carbon site designated by # in formula I are preferred. When R11 is hydrogen, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula I are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 0 or 1, the epimers with the S absolute configuration at the chiral carbon site designated by an asterisk in formula I are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 2, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula I are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 0, the cis epimers [(2S, 3S) absolute configuration in the axetidine ring] are particularly preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 1, the cis epimers [(2S, 4R) absolute configuration in the pyrrolidine ring ] are particularly preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 2, the cis epimers [(2R, 5R) absolute configuration in the piperidine ring ] are particularly preferred.
Unless otherwise indicated, the alkyl, alkenyl, and alkynyl groups referred to herein, as well as the alkyl and alkylene moieties of other groups referred to herein (e.g. alkoxy), may be linear or branched, and they may also be cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear or branched and contain cyclic moieties.
Preferred compounds of the invention are compounds of the formula I wherein W is (i), (ii), or (iii); n is 1; m is 1; R1 is hydrogen, C1 to C3 alkyl, or xe2x80x94CH2CH2OCH3; R2 is hydrogen; and R3 is hydrogen or xe2x80x94CH2Ph (Ph=phenyl). Of the foregoing preferred compounds, the epimers with the S optical configuration at the chiral carbon designated by # in formula I are more preferred. Of the foregoing preferred compounds, when R11 is hydrogen, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula I are more preferred. Of the foregoing preferred compounds, when R11 is xe2x80x94OR12 or xe2x80x94NHCOR12, the epimers with the S absolute configuration at the chiral carbon site designated by an asterisk in formula I are more preferred. Of the foregoing compounds, when R11 is xe2x80x94OR12 or xe2x80x94NHCOR12, the cis epimers [(2S, 4R) absolute configuration in the pyrrolidine ring] are particularly preferred.
The following compounds are particularly preferred:
3-[(N-2-Methoxyethyl)pyrrolldin-2R-ylmethyl]-5-(2-oxo-1,3-oxazolidin-4S-ylmethyl)-1H-indole;
5-(2-Oxo-1,3-oxazolidin-4S-ylmethyl)-3-(pyrrolidin-2R-ylmethyl)-1H-indole; and
3-(N-Methylpyrrolidin-2R-ylmethyl)-5-(2-oxo-1,3-oxazolidin-4R,S-ylmethyl)-1H-indole.
The present invention also relates to a pharmaceutical composition for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition and a pharmaceutically acceptable carrier.
The present invention also relates to a method for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising administering to a mammal (e.g., a human) requiring such treatment an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition.
The present invention also relates to a pharmaceutical composition for treating disorders arising from deficient serotonergic neurotransmission (e.g., depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders) comprising administering to a mammal (e.g., a human) requiring such treatment an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition.
The present invention also relates to a method for treating disorders arising from deficient serotonergic neurotransmission (e.g., depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders) comprising administering to a mammal (e.g., a human) requiring such treatment an amount of a compound of the formula I of a pharmaceutically acceptable salt thereof effective in treating such condition.
The present invention also relates to a compound of the formula 
where W is 
n is 0, 1, or 2; m is 0, 1, 2, or 3; Y and G are each independently oxygen or sulfur; Z is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NH, or xe2x80x94CH2; R2 and R3 are each independently hydrogen, C1 to C8 alkyl, aryl, C1 to C3 alkylaryl, and C1 to C3 alkylheteroaryl; R3 C1 to C8 alkyl, aryl, or C1 to C3 alkylaryl (preferably benzyl); R1 is hydrogen, xe2x80x94OR12, or xe2x80x94NHCOR12; R12 is hydrogen, C1 to C6 alkyl, aryl, or C1 to C3 alkyl-aryl; a first chiral carbon is designated by an asterisk; a second chiral carbon is designated by #; and the above aryl groups and the aryl moieties of the above alkyl-aryl groups are independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C1 to C4 alkyl, halogen (e.g. fluorine, chlorine bromine or iodine), hydroxy, cyano, carboxamido, nitro, and C1 to C4 alkoxy. The epimers with the S absolute configuration at the chiral carbon site designated by # in formula II are preferred. When R11 is hydrogen, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula II are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 0 or 1, the epimers with the S absolute configuration at the chiral carbon site designated by an asterisk in formula II are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 2, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula II are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 0, the cis epimers [(2S, 3S) absolute configuration in the azetidine ring] are particularly preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 1, the cis epimers [(2S, 4R) absolute configuration in the pyrrolidine ring] are particularly preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 2, the cis epimers [(2R, 5R) absolute configuration in the piperidine ring] are particularly preferred. The compounds of formula II are useful as intermediates in preparing compounds of formula I.
The present invention also relates to a compound of the formula 
where W is 
n is 0, 1, or 2; m is 0, 1, 2, or 3; Y and G are each independently oxygen or sulfur; Z is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NH, or xe2x80x94CH2; R2 and R3 are each independently hydrogen, C1 to C6 alkyl, aryl, C1 to C3 alkylaryl, or C1 to C3 alkylheteroaryl; R5 is C1 to C6 alkyl, aryl, or C1 to C3 alkylaryl (preferably benzyl); R6 is halogen [preferably bromide]; R7 is xe2x80x94COCF3, xe2x80x94SO2CH3. xe2x80x94SO2Ph, or xe2x80x94CO2C(CH3)3; R11 is hydrogen, xe2x80x94OR12, or xe2x80x94NHCOR12; R12 is hydrogen, C1 to C6 alkyl, aryl, or C1 to C3 alkyl-aryl; a first chiral carbon is designated by an asterisk; a second chiral carbon is designated by #; and the above aryl groups and the aryl moieties of the above alkyl-aryl groups are independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C1 to C4 alkyl, halogen (e.g. fluorine, chlorine bromine or iodine), hydroxy, cyano, carboxamido, nitro, and C1 to C4 alkoxy. The epimers with the S absolute configuration at the chiral carbon site designated by # in formula III are preferred. When R11 is hydrogen, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula III are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 0 or 1, the epimers with the S absolute configuration at the chiral carbon site designated by an asterisk in formula III are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 2, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula III are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 0, the cis epimers [(2S, 3S) absolute configuration in the azetidine ring] are particularly preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 1, the cis epimers [(2S, 4R) absolute configuration in the pyrrolidine ring] are particularly preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 2, the cis epimers [(2R, 5R) absolute configuration in the piperidine ring] are particularly preferred. The compounds of formula III are useful as intermediates in preparing compounds of formula II.
The present invention also relates to a compound of the formula 
n is 0, 1, or 2; J is xe2x80x94OH or xe2x80x94CO2R13; R1 is hydrogen, C1 to C8 alkyl, substituted C1 to C8 alkyl substituted with one hydroxy, C3 to C6 alkenyl, C3 to C8 alkynyl, aryl, C1 to C3 alkylaryl, C1 to C3 alkylheteroaryl, or xe2x80x94Qxe2x80x94R4; R4 is cyano, trifluoromethyl, xe2x80x94COR9, xe2x80x94CO2R9, xe2x80x94CONR9R10, xe2x80x94OR9, xe2x80x94SO2NR9R10, or xe2x80x94S(O)4R9; R9 and R10 are each independently hydrogen, C1 to C8 alkyl, C1 to C3 alkylaryl, aryl, or R8 and R10 may together be taken to form a three- to seven-membered alkyl ring or a three- to seven-membered heteroalkyl ring having 1 heteroatom of O; R11 is hydrogen, xe2x80x94OR12, or xe2x80x94NHCOR12; R12 is hydrogen, C1 to C8 alkyl, aryl, or C1 to C3 alkyl-aryl; R13 is C1 to C6 alkyl, aryl, or C1 to C3 alkyl-aryl; q is 0, 1, or 2; Q is C1 to C3 alkyl; a first chiral carbon is designated by an asterisk; a second chiral carbon is designated by #; and the above aryl groups and the aryl moieties of the above alkyl-aryl groups are independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C1 to C4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro, and C1 to C4 alkoxy. The epimers with the S absolute configuration at the chiral carbon site designated by # in formula XVII are preferred. When R11 is hydrogen, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula XVII are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 0 or 1, the epimers with the S absolute configuration at the chiral carbon site designated by an asterisk in formula XVII are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 2, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula XVII are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 0, the cis epimers [(2S, 3S) absolute configuration in the azetidine ring] are particularly preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 1, the cis epimers [(2S, 4R) absolute configuration in the pyrrolidine ring] are particularly preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 2, the cis epimers [(2R, 5R) absolute configuration in the piperidine ring] are particularly preferred. The compounds of formula XVII are useful as intermediates in preparing compounds of formula I.
The present invention also relates to a compound of the formula 
n is 0, 1, or 2; R1 is hydrogen, C1 to C8 alkyl, substituted C1 to C8 alkyl substituted with one hydroxy, C3 to C8 alkenyl, C3 to C8 alkynyl, aryl, C1 to C3 alkylaryl, C1 to C3 alkylheteroaryl, or xe2x80x94Qxe2x80x94R4; R8 is C1 to C8 alkyl, aryl, or C1 to C3 alkylaryl; R4 is cyano, trifluoromethyl, xe2x80x94COR9, xe2x80x94CO2R5, xe2x80x94CONR9R10, xe2x80x94OR9, xe2x80x94SO2NR9R10, or xe2x80x94S(O)4R9; R9 and R10 are each independently hydrogen, C1 to C8 alkyl, C1 to C3 alkylaryl, aryl, or R9 and R10 may together be taken to form a three- to seven membered alkyl ring or a three- to seven-membered heteroalkyl ring having 1 heteroatom of O; R11 is hydrogen, xe2x80x94OR12, or xe2x80x94NHCOR12; R12 is hydrogen, C1 to C6 alkyl, aryl, or C1 to C6 alkyl, aryl, or C1 to C3 alkyl-aryl; R13 is C1 to C6 alkyl, aryl, or C1 to C3 alkyl-aryl; q is 0, 1, or 2; Q is C1 to C3 alkyl; a first chiral carbon is designated by an asterisk; and the above aryl groups and the aryl moieties of the above alkyl-aryl groups are independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C1 to C4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro, and C1 to C4 alkoxy. The epimers with the S absolute configuration at the chiral carbon site designated by ∩ in formula XIV are preferred. When R11 is hydrogen, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula XIV are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 0 or 1, the epimers with the S absolute configuration at the chiral carbon site designated by an asterisk in formula XIV are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 2, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula XIV are preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 0, the cis epimers [(2S, 3S) absolute configuration in the azetidine ring] are particularly preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 1, the cis epimers [(2S, 4R) absolute configuration in the pyrrolidine ring ] are particularly preferred. When R11 is xe2x80x94OR12 or xe2x80x94NHCOR12 and n is 2, the cis epimers [(2R, 5R) absolute configuration in the piperidine ring ] are particularly preferred. The compounds of formula XIV are useful as intermediates in preparing compounds of formula XVII.